Steroid, thyroid and retinoid hormones produce a diverse array of physiologic effects through the regulation of gene expression. Upon entering the cell, these hormones bind to a unique group of intracellular nuclear receptors which have been characterized as ligand-dependent transcription factors. This complex then moves into the nucleus where the receptor and its cognate ligand interact with the transcription preinitiation complex affecting its stability and ultimately the rate of transcription of the target genes.
The interactions of the liganded receptor with the specific elements in the promoter region are mediated by two classes of molecules; corepressors, which inhibit transactivation and coactivators, which enhance transactivation.
SRC-1 (also known as steroid receptor coactivator-1, F-SRC-1 and NcoA-1) is a member of the growing family of transcriptional coactivators. SRC-1 was first isolated as a protein that interacted with and enhanced human progesterone receptor (hPR) transcriptional activity in a hormone-dependent manner without altering the basal activity of the promoter (Onate et al., Science, 1995, 270, 1354-1357). Subsequently, SRC-1 has been shown to enhance the transcriptional ability of other steroid receptors including the estrogen receptor (Kalkhoven et al., Embo J., 1998, 17, 232-243), glucocorticoid receptor (Onate et al., Science, 1995, 270, 1354-1357), thyroid hormone receptor (Jeyakumar et al., Mol. Endocrinol., 1997, 11, 755-767), retinoic acid receptor (Yao et al., Proc. Natl. Acad. Sci. U.S.A., 1996, 93, 10626-10631) and retinoid X receptor (Westin et al., Nature, 1998, 395, 199-202), all in a ligand-dependent manner.
SRC-1 contains an intrinsic histone acetyltransferase activity specific for histones H3 and H4. It was proposed that this intrinsic activity allows the protein to disrupt the compacted chromatin structure and enhance the formation of a stable preinitiation complex (Spencer et al., Nature, 1997, 389, 194-198).
SRC-1 has also been shown to mediate transactivation through interactions with c-Jun, c-Fos and NF-kappa-B subunits (Lee et al., J. Biol. Chem., 1998, 273, 16651-16654; Na et al., J. Biol. Chem., 1998, 273, 10831-10834).
Tissue distribution studies showed that SRC-1 message is expressed at high levels in the heart, placenta, skeletal muscle, and pancreas but at very low levels in the lung, liver and kidney (Li and Chen, J. Biol. Chem., 1998, 273, 5948-5954). In the rat, a gender-related difference in expression was found in the anterior pituitary, with females expressing 40% less SRC-1 than males (Misiti et al., Endocrinology, 1998, 139, 2493-2500).
Variations in SRC-1 levels have recently been used as a predictive marker of tamoxifen response in recurrent breast cancer. These studies showed that SRC-1 levels were lower in tumors from patients that did not respond to tamoxifen treatment, suggesting that high levels of SRC-1 indicated a favorable response to tamoxifen (Berns et al., Breast Cancer Res. Treat., 1998, 48, 87-92).
To date, strategies aimed at inhibiting SRC-1 function have involved the use of mutant forms of the protein and gene knock-outs in mice.
By localizing functional domains within the protein, it was demonstrated that a truncated version of the protein lacking the C-terminal domain could act as a dominant-negative repressor of transcription (Onate et al., Science, 1995, 270, 1354-1357). These results lend further support to the role of SRC-1 as a coactivator.
In studies of mice lacking the SRC-1 gene, both hetero-and homozygous SRC-1 null mice appeared to be normal with no obvious external differences from the wild-type. However, internal organs such as the uterus, prostate, testis and mammary glands showed decreased growth and development in response to steroid hormones. These results indicated that SRC-1 is required for efficient hormone action in vivo (Xu et al., Science, 1998, 279, 1922-1925).
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of SRC-1. Consequently, there remains a long felt need for additional agents capable of effectively inhibiting SRC-1 function. Antisense oligonucleotides, therefore, may provide a promising new pharmaceutical tool for the effective and specific modulation of SRC-1 expression.